Atmospheric pressure ionization has evolved into an indispensable analytical tool in mass spectrometry and applications in life sciences with a significant impact in areas spanning from drug discovery to protein structure and function as well as the emerging field of systems biology applied to biomedical scientific research. The advent of atmospheric pressure ionization and particularly electrospray enabled the analysis of intact macromolecular ions under native conditions which offers a wealth of information to many different disciplines of science. The generation of intact ionic species is accomplished at or near atmospheric pressure whereas the determination of molecular mass is accomplished at high vacuum. Therefore transfer efficiency of ions generated at high pressure toward consecutive regions of the mass spectrometer operated at reduced pressure is a critical parameter, which determines instrument performance in terms of sensitivity.
Electrospray ionization (“ESI”) is the prevailing method for generation of gas phase ions where ions in solution are sprayed typically under atmospheric pressure and in the presence of a strong electric field. Charged droplets released from the ESI emitter tip undergo a recurring process of evaporation and fission ultimately releasing ions sampled by an inlet capillary or other types of inlet apertures. The inlet aperture forms the interface of the instrument and represents a physical barrier between the high pressure ionization region and the fore vacuum region normally operated at 1 mbar background pressure. The size of the inlet aperture or capillary employed to admit ions in the fore vacuum is typically limited to ˜0.5 mm in diameter to establish the pressure differential preferred for the existing ion optical components to be operable and transport ions to subsequent lower pressure vacuum regions efficiently. Consequently, sampling efficiency of the spray containing charged droplets and bare ions using standard interface designs is limited to <1% and has a profound effect on instrument sensitivity.
The design of a high transmission interface for efficient transportation of ions from atmospheric pressure into the fore vacuum region of a mass spectrometer has grown into a challenging problem. One approach involves increasing pumping speed to accommodate relatively small increments in the size of the inlet aperture. Although increasing the inlet aperture appears a rather straight forward solution the inefficient heat transfer and incomplete desolvation of the electrospray droplets are not easily addressed. Furthermore, the cost related to the increased pumping speed becomes considerable. Efforts for improved ion transfer efficiency are also directed toward the development of novel ion optical devices operable at elevated pressure. The ion funnel has been operated successfully at pressures as high as 30 mbar, nevertheless increments in the size of the inlet aperture remain marginal. In yet another design of an interface a multi-inlet capillary configuration is implemented in an effort to sample a larger area of the electrospray plume. Using this type of a novel multi-inlet system enhanced transfer efficiency is claimed, however, the ion losses at the interface are still severe since the reduction in pressure from atmospheric to near or below 10 mbar requires the cross sectional area of the inlet to be kept small. Reducing pressure by approximately two orders of magnitude in a single step is inevitably associated with severe ion losses due to the narrow aperture or other types of multi-inlet system configurations employed. Indeed, these approaches do not address the underlying loss mechanisms arising from diffusion losses, space charge losses, and high gas velocity at the exit of the capillary/capillaries or skimmer. This latter problem can result in a high value for the turbulent velocity ratio (“TVR”) and the high gas speed prevents effective focusing via an electrical field.
In an entirely different approach a multi-chamber configuration has been disclosed to operate using enlarged apertures and where pressure is reduced progressively from the fore vacuum pressure of ˜5 mbar to regions of lower pressure. Over this pressure range ions can be guided by RF electrical fields. Whilst use of a series of vacuum regions to reduce pressure progressively may enhance ion transfer efficiency to the high vacuum region, it does not address the problem of the majority of the ions being lost at the interface where a single inlet aperture is employed to sustain a large drop in pressure which is typically from 1 bar down to 5 mbar.
U.S. Pat. No. 6,943,347 discloses a tube for accepting gas-phase ions and particles contained in a gas by allowing substantially all the gas-phase ions and gas from an ion source at or greater than atmospheric pressure to flow into the tube and be transferred to a lower pressure region. Transport and motion of the ions through the tube is determined by a combination of viscous forces exerted on the ions by the flowing gas molecules and electrostatic forces causing the motion of the ions through the tube and away from the walls of the tube. More specifically, the tube is made up of stratified elements, wherein DC potentials are applied to the elements so that the DC voltage on any element determines the electric potential experience by the ions as they pass through the tube. A precise electrical gradient is maintained along the length of the stratified tube to insure the transport of the ions.
WO2008055667 discloses a method of transporting gas and entrained ions between higher and lower pressure regions of a mass spectrometer comprises providing an ion transfer conduit 60 between the higher and lower pressure regions. The ion transfer conduit 60 includes an electrode assembly 300 which defines an ion transfer channel. The electrode assembly 300 has a first set of ring electrodes 305 of a first width D1, and a second set of ring electrodes of a second width D2 (=D1) and interleaved with the first ring electrodes 305. A DC voltage of magnitude V1 and a first polarity is supplied to the first ring electrodes 205 and a DC voltage of magnitude V2 which may be less than or equal to the magnitude of V1 but with an opposed polarity is applied to the second ring electrodes 310. The pressure of the ion transfer conduit 60 is controlled so as to maintain viscous flow of gas and ions within the ion transfer channel.
WO2009/030048 discloses a mass spectrometer including a plurality of guide stages for guiding ions between an ion source and an ion detector along a guide axis. Each of the guide stages is contained within one of a plurality of adjacent chambers. Pressure in each of the plurality of chambers is reduced downstream along the guide axis to guide ions along the axis. Each guide stage may further include a plurality of guide rods for producing a containment filed for containing ions about the guide axis, as they are guided to the detector.
U.S. Pat. No. 7,064,321 (also published as US2005/006579) discloses an ion funnel that screens ions from a gas stream flowing into a differential pump stage of a mass spectrometer, and transfers them to a subsequent differential pump stage. The ion funnel uses apertured diaphragms between which gas escapes easily. Holders for the apertured diaphragms are also provided that offer little resistance to the escaping gas while, at the same time, serving to feed the RF and DC voltages
U.S. Pat. No. 8,610,054 discloses an ion analysis apparatus for conducting differential ion mobility analysis and mass analysis. In embodiments, the apparatus comprises a differential ion mobility device in a vacuum enclosure of a mass spectrometer, located prior to the mass analyser, wherein the pumping system of the apparatus is configured to provide an operating pressure of 0.005 kPa to 40 kPa for the differential ion mobility device, and wherein the apparatus includes a digital asymmetric waveform generator that provides a waveform of frequency of 50 kHz to 25 MHz. Examples demonstrate excellent resolving power and ion transmission. The ion mobility device can be a multipole, for example a 12-pole and radial ion focusing can be achieved by applying a quadrupole field to the device in addition to a dipole field.
US2009/127455 discloses ion guides for use in mass spectrometry and the analysis of chemical samples. The disclosure includes a method and apparatus for transporting ions from a first pressure region in a mass spectrometer to a second pressure region therein. More specifically, the disclosure provides a segmented ion funnel for more efficient use in mass spectrometry (particularly with ionization sources) to transport ions from the first pressure region to the second pressure region.
“A multicapillary inlet jet disruption electrodynamic ion funnel interface for improved sensitivity using atmospheric pressure ion sources”, Kim T, Tang K, Udseth H R, Smith R D/Anal Chem. 2001 Sep. 1; 73(17):4162-70 discloses a multicapillary inlet jet disruption electrodynamic ion funnel interface for improved sensitivity using atmospheric pressure ion sources.
PCT/GB2015/051569 (currently unpublished, but relevant extracts from which are included in the present disclosure as an Annex) discloses an ion transfer apparatus comprising a plurality of pressure control chambers. This ion transfer apparatus was designed to provide an improved interface design capable of transferring ions into the fore vacuum region with greater efficiency while maintaining effective desolvation of charged droplets.
The present invention has been devised in light of the above considerations.
In some embodiments, the present invention may provide improvements to the ion transfer apparatus described in PCT/GB2015/051569 (currently unpublished, but relevant extracts from which are included in the present disclosure as an Annex).